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Ann Neurol. 2015 Jun;77(6):972-86. doi: 10.1002/ana.24395. Epub 2015 Mar 28.

Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes.

Author information

1
Department of Neurology, Medical University of Vienna, Vienna, Austria.
2
Institute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany.
3
Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany.
4
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
5
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
6
RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
7
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
8
Private Practice of Pediatrics, Vienna, Austria.
9
Department of Pediatrics, Medical University of Graz, Graz, Austria.
10
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
11
Department of Neuropediatrics, St Anna Children's Hospital, Vienna, Austria.
12
Department of Pediatrics, SMZ Süd - Kaiser-Franz-Josef-Hospital, Vienna, Austria.
13
Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
14
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
15
Departments of Epidemiology, Neurology, and Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
16
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
17
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
18
Institute of Human Genetics, University of Cologne, Cologne, Germany.
19
Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
20
Braunschweig University of Technology, Zoological Institute, Division of Cell Physiology, Braunschweig, Germany.
21
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

Abstract

OBJECTIVE:

To test whether mutations in γ-aminobutyric acid type A receptor (GABAA -R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE).

METHODS:

We performed exome sequencing to compare the frequency of variants in 18 GABAA -R genes in 204 European patients with RE/ARE versus 728 platform-matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering, and receptor function.

RESULTS:

Of 18 screened GABAA -R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5 of 204, 2.45%) in comparison to controls (1 of 723, 0.14%; odds ratio = 18.07, 95% confidence interval = 2.01-855.07, p = 0.0024, pcorr  = 0.043). We identified a GABRG2 splice variant (c.549-3T>G) in 2 unrelated patients as well as 3 nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a post-translational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant γ2 subunit.

INTERPRETATION:

The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants.

PMID:
25726841
DOI:
10.1002/ana.24395
[Indexed for MEDLINE]

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